The objectives of the proposed research can be divided into six general areas: 1. Definition of the pathologic features of the proximal tubular lesion of gentamicin toxicity and correlation with the dose and duration of therapy. This will be done by light and electron microscopy of renal tissue from rats. 2. Evaluation of the influences of sodium balance, the renal pressor system, diuretic therapy, age and prior renal disease on the nephrotoxic effects of gentamicin in the rat model. 3. Determination of the basic mechanism of toxicity by studies of cellular localization of gentamicin with indirect immunofluorescent techniques, effect of gentamicin on uptake of PAH into renal cortical slices, and the kinetics of gentamicin transport in vitro. 4. Characterization of renal handling of gentamicin and its pharmacokinetics. This will involve development of a satisfactory tissue gentamicin assay and determination of the extent of gentamicin to plasma proteins. Application of these data will be applied to treatment of urinary infections in man with reduced GFR. 5. Development of sensitive laboratory techniques to monitor therapy such as urinary excretion of lysosomal enzymes and Beta2 microglobulin. Correlations of these urinary parameters with clinical renal failure and pathologic changes will be made in man and experimental rats. 6. Determination of the possible preventative effects of quinine, mannitol, PAH by impeding proximal tubular cell uptake of gentamicin in experimental rats and man.